Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Patent
1994-11-14
1997-07-15
Daus, Donald G.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
546 49, 546 56, A61K 3147
Patent
active
056483600
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention mimes to pentacyclic compounds, pharmaceutical compositions comprising such compounds, and to their use as antihistamines and as platelet-activating factor (PAF) antagonists.
SUMMARY OF THE INVENTION
Novel compounds of the present invention are represented by the structural formula I: ##STR2## or a pharmaceutically acceptable salt thereof, wherein:
X is hydrogen, halo, --CF.sub.3 or lower alkyl with hydrogen, halo, --CF.sub.3 or --CH.sub.3 being preferred, the phenyl ring contains 1,2, or 3 X substituents and when there are 2 or 3 X substituents said substituents are the same or different;
Y is --(CH.sub.2).sub.n --, wherein n is 0, 1, 2 or 3, --C(O)--, --CH.sub.2 C(O)--, --CH.sub.2 CH.sub.2 C(O)-- or --CH(OH)--;
A is --N(R)-- and B is --CH.sub.2 --, or A is --CH.sub.2 -- and B is --N(R)--;
R is hydrogen, lower alkyl, lower alkanoyl, --CO.sub.2 R.sup.1, ##STR3##
R.sup.1 is hydrogen, lower alkyl or --CH.sub.2 CCl.sub.3 ; and
- - - - represents an optional double bond, with the proviso that the ring containing Y has only one optional double bond--i.e., when present, there can only be one double bond in the ring containing Y.
Compounds represented by formula I include compounds of the formula: ##STR4## wherein X, Y, A, B and the dotted line - - - are as defined for formula I above.
Compounds represented by formula I also include compounds of the formula: ##STR5## wherein X, A, B and the dotted line - - - are as defined for formula I above.
Compounds represented by formula Iii include compounds of formula XIV: ##STR6## wherein Q is .dbd.O or --OH, and X, A, B and the dotted line - - - are as defined for formula I.
Preferred compounds of the invention are those wherein Y is --(CH.sub.2).sub.n -- wherein n is 1, --C(O)-- or .dbd.CH-- (i.e., wherein Y is --(CH.sub.2).sub.n --, n is 1 and the optional adjacent double bond is present). Another group of preferred compounds is that wherein A is --CH.sub.2 -- and B is --N(R)--. Also preferred are compounds wherein X is halo, more preferably chloro. Preferred values for R are lower alkyl, especially methyl; acetyl; ethyl carboxylate; and pyridylcarbonyl N-oxide.
Especially preferred are compounds of formula I wherein X is chloro, Y is --CH.sub.2 --, --C(O)-- or .dbd.CH--, A is --CH.sub.2 --, B is --N(R)-- and R is methyl, acetyl, ethylcarboxylate or pyridylcarbonyl N-oxide.
The invention also includes a pharmaceutical composition which comprises a compound of formula I in combination with a pharmaceutically acceptable carrier.
The invention further includes a method of treating allergy or inflammation in a mammal which comprises administering an effective amount of a compound of formula I to a mammal in need of such treatment.
DETAILED DESCRIPTION
As used herein, the term "lower alkyl" means straight or branched carbon chains of 1 to 6 carbon atoms.
"Halo" refers to fluoro, chloro, bromo or iodo.
"Lower alkanoyl" refers to lower alkyl carbonyl radicals wherein lower alkyl is as defined above.
When Y is --CH.sub.2 (CO)-- or --CH.sub.2 CH.sub.2 C(O)--, the methylene group is attached to the piperidino-ring portion of the molecule and the carbonyl group is attached to the phenyl-ring portion.
Compounds of the invention may exist in isomeric forms. Due to the possible presence of several chiral centers, various enantiomers and/or diastereomers can be present. All such isomers are contemplated as being part of this invention, both in pure form and in admixture, including racemic mixtures.
The compounds of the invention of formula I can exist in unsolvated as well as solvated forms, including hydrated forms, e.g., hemihydrate. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol and the like are equivalent to the unsolvated forms for purposes of the invention.
The phenyl ring in the structure of formula I may contain one, two or three X substituents. In compounds where there is more than one such substituent, they may be the same or different. Thus, compounds having combinati
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Merck Index, 10th Edition, Rahuay, NJ, 1983 page on R33.
Carruthers Nicholas I.
Kaminski James J.
Wong Shing-Chun C.
Daus Donald G.
Jeanette Henry C.
Schering Corporation
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